Abstract Infections caused by Gram-positive pathogens, including Clostridium difficile, are a leading cause of mortality. Three species?methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae and vancomycin-resistant enterococcus (VRE)?are responsible annually for at least 84% of deaths due to antibiotic- resistant infections. C. difficile is the most common and costly healthcare-associated infection with an estimated 29,000 deaths annually. Only one new antibiotic, fidaxomicin, has been approved in the last 30 years for treatment of C. difficile infection and recurrence rates are still high for infections involving hypervirulent strains. There is a desperate need for new drugs with improved efficacy. Unlike the costly and time-consuming process of de novo drug discovery, drug repurposing is a novel method to reduce the time, cost and risk associated with drug innovation. Studies proposed in this application focus on repurposing one non-antimicrobial approved drug, auranofin, and one clinical molecule, ebselen. These two agents possess potent antibacterial activity, in a low nano molar concentration achievable at a clinical range, against multidrug-resistant pathogens, including MRSA, VRE, and C. difficile. We have demonstrated (in vitro and in vivo) that both drugs are superior to drugs of choice and are capable of 1) killing intracellular and persistent MRSA, 2) disrupting adherent staphylococcal biofilms, 3) suppressing key virulence factors including toxin production, 4) reducing excessive host-inflammatory responses associated with these toxins, 5) significantly reducing both the bacterial load and levels of the pro- inflammatory cytokines in MRSA skin lesions, and 6) enhancing wound healing. Both drugs have additional advantageous qualities against C. difficile including; a) potent activity achievable in a clinical range, b) inhibiting toxin production, c) neutralizing C. difficile toxins by inhibiting the cysteine protease domain, d) inhibiting spore formation, e) inhibiting IL-8 release and protecting cells from effect of toxins, f) preventing intestinal colonization of VRE, and were g) superior to drugs of choice in in vitro testing. The fact that auranofin has been granted orphan-drug status from the FDA for treatment of intestinal amebiasis, and is currently in a Phase II clinical trial for treatment of intestinal giardiasis, further validates our approach. Our overall goal in this application is to further validate auranofin and ebselen as potential treatments for superficial, systemic and intestinal infections caused by multidrug-resistant bacterial pathogensand C. difficile. Our findings in MRSA, VRE and C. difficile will be broadly relevant to other pathogens and may offer a safe, effective, and quick supplement to current approaches for treating bacterial infections.